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    Clinical Trial Results:
    Scheduling nab-paclItaxEl with GEmcitabine (SIEGE): Randomised phase II trial to investigate two different schedules of nab-paclitaxel (Abraxane) combined with gemcitabine as first line treatment for metastatic pancreatic ductal adenocarcinoma

    Summary
    EudraCT number
    2013-001868-40
    Trial protocol
    GB  
    Global end of trial date
    21 Mar 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    11 Apr 2018
    First version publication date
    11 Apr 2018
    Other versions
    Summary report(s)
    SIEGE_AdverseEvents_listingbycategory
    Full SAE lisiting

    Trial information

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    Trial identification
    Sponsor protocol code
    AX-PANC-PI-0101 (SIEGE)
    Additional study identifiers
    ISRCTN number
    ISRCTN71070888
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    IRAS Project I.D.: 130640, UK REC Reference: 13/NI/0143
    Sponsors
    Sponsor organisation name
    Cambridge University Hospitals NHS Foundation Trust
    Sponsor organisation address
    Hills Road , Cambridge , United Kingdom, CB2 0QQ
    Public contact
    Richard Skells, Cambridge Unversity Hospitals NHS Foundation Trust, +44 (0) 1223349707, richard.skells@addenbrookes.nhs.uk
    Scientific contact
    Pippa Corrie , Cambridge Unversity Hospitals NHS Foundation Trust, +44 (0) 1223349707, pippa.corrie@addenbrookes.nhs.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    15 Mar 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Mar 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Mar 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the trial was to investigate the outcome of sequential administration of nab-paclitaxel (Abraxane) combined with gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma (PDAC) in terms of progression-free survival.
    Protection of trial subjects
    The study was approved by a Research Ethics Committee and received authorisation from the Medicines and Healthcare Products Regulatory Agency. Patients received verbal and written information prior to consenting to the trial and had the time to consider their participation and opportunity to ask questions. Patient data and samples were anonymised so that their information was kept confidential. The SIEGE Protocol mandated the use of white blood cell growth factors (G-CSF) after every episode of Febrile Neutropenia, and was recommended for patients in episodes of higher grade neutropenia. Furthermore, dose modifications were also mandated for patients with hematological and non-hematological toxicities depending on the event, and the grade of such event, as detailed in the study Protocol. Particular guidance was given regarding Hepatic Impairment and Peripheral Neuropathy events, in line with the nab-paclitaxel Reference Safety Information. Any occurrence of life-threatening toxicity or hypersensitivity reaction mandated immediate discontinuation from treatment. Grade 4 non-hematological toxicity also mandated discontinuation from treatment, unless the investigator deemed that the patient continued to benefit from the treatment. Serious Adverse Events were routinely reviewed by Sponsor and the ISDMC to ensure that all sites provided adequate supportive therapies when required and were compliant with the safety aspects of the SIEGE trial Protocol.
    Background therapy
    Metastatic Pancreatic Ductal Adenocarcinoma (PDAC) carries a poor prognosis. Gemcitabine (GEM) is the international standard of care. Combination therapy with FOLFIRINOX has previous demonstrated a superior progression-free survival, compared to GEM alone. However the side effects associated with this combination means that is may not be suitable for all mPDAC patients. Nab-paclitaxel (Abraxane or ABX) is an albumin-bound formulation of paclitaxel. PDAC is well recognised to be a stromal-rich tumour which expresses high amounts of secreted protein acidic and rich in cysteine (SPARC); SPARC may act as an albumin-binding protein capable of sequestering ABX to concentrate the drug intratumourally. Previous trials using a combination therapy of ABX and GEM reported lower levels of neutropenia than with FOLFIRINOX, and generally appeared to be more widely tolerated
    Evidence for comparator
    Whilst the interaction between Abraxane and Gemcitabine is not clear, studies in mouse models of PDAC suggest that delivery of ABX 24 hours prior to GEM might result in higher intra-tumoural GEM concentrations. Thus, scheduling of these two drugs may be critical to optimising clinical benefit.
    Actual start date of recruitment
    23 Jan 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 146
    Worldwide total number of subjects
    146
    EEA total number of subjects
    146
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    69
    From 65 to 84 years
    77
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    146 participants were recruited between 24th March 2014 and 23rd March 2016 across 19 UK sites. Recruitment was steady and consistent throughout, with the recruitment half-way point achieved in March 2015 as expected.

    Pre-assignment
    Screening details
    186 Patients consented to the trial with suspected metastatic pancreatic adenocarcinoma deemed fit to treat. 40 Screen Failures. 34 deemed ineligible (13 pathological, 11 lab criteria, 10 poor performance) and 6 patients declined (2 declined biopsy, 2 travel, 1 alternative treatment and 1 no treament) 146 Patients were randomised

    Pre-assignment period milestones
    Number of subjects started
    186 [1]
    Number of subjects completed
    146

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Protocol deviation: 34
    Reason: Number of subjects
    Patient Decision: 6
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Included in this number is the patients consented and screened in the study. Only 146 patients were enrolled in the study.
    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    N/A - not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Concomitant
    Arm description
    Patients on the control (concomitant) arm received intravenous nab-paclitaxel at 125mg/m2 immediately followed by intravenous gemcitabine at 1000mg/m2 on Days 1, 8 and 15 of a 4-weekly cycle for 6 cycles. Research bloods were taken from these patients on Cycle 1 Day 1, 8 and 15 in the first instance, and then on Day 1 of each subsequent cycle.
    Arm type
    Active comparator

    Investigational medicinal product name
    nab-Paclitaxel
    Investigational medicinal product code
    ABX
    Other name
    Abraxane
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients on the control (concomitant) arm received intravenous nab-paclitaxel at 125mg/m2 immediately followed by intravenous gemcitabine at 1000mg/m2 on Days 1, 8 and 15 of a 4-weekly cycle for 6 cycles.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    GEM
    Other name
    Gemzar
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients on the control (concomitant) arm received intravenous nab-paclitaxel at 125mg/m2 immediately followed by intravenous gemcitabine at 1000mg/m2 on Days 1, 8 and 15 of a 4-weekly cycle for 6 cycles. Research bloods were taken from these patients on Cycle 1 Day 1, 8 and 15 in the first instance, and then on Day 1 of each subsequent cycle.

    Arm title
    Sequential
    Arm description
    Patient on the research (sequential) arm received intravenous nab-paclitaxel at 125mg/m2 on Day 1, 8 and 15, and intravenous gemcitabine at 1000mg/m2 on Day 2, 9 and 16 of a 4-weekly cycle for 6 cycles. Research bloods were taken from these patients on Cycle 1 Day 1, 2, 8, 9, 15 and 16 in the first instance, and then on Day 1 of each subsequent cycle.
    Arm type
    Experimental

    Investigational medicinal product name
    nab-Paclitaxel
    Investigational medicinal product code
    ABX
    Other name
    Abraxane
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patient on the research (sequential) arm received intravenous nab-paclitaxel at 125mg/m2 on Day 1, 8 and 15, and intravenous gemcitabine at 1000mg/m2 on Day 2, 9 and 16 of a 4-weekly cycle for 6 cycles.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    GEM
    Other name
    Gemzar
    Pharmaceutical forms
    Powder for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patient on the research (sequential) arm received intravenous nab-paclitaxel at 125mg/m2 on Day 1, 8 and 15, and intravenous gemcitabine at 1000mg/m2 on Day 2, 9 and 16 of a 4-weekly cycle for 6 cycles.

    Number of subjects in period 1
    Concomitant Sequential
    Started
    75
    71
    Completed
    21
    30
    Not completed
    54
    41
         Protocol deviation
    1
    1
         Death
    6
    3
         Patient Decision
    4
    2
         Adverse event, non-fatal
    20
    22
         Progressive Disease
    23
    11
         Consent withdrawn by subject
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Concomitant
    Reporting group description
    Patients on the control (concomitant) arm received intravenous nab-paclitaxel at 125mg/m2 immediately followed by intravenous gemcitabine at 1000mg/m2 on Days 1, 8 and 15 of a 4-weekly cycle for 6 cycles. Research bloods were taken from these patients on Cycle 1 Day 1, 8 and 15 in the first instance, and then on Day 1 of each subsequent cycle.

    Reporting group title
    Sequential
    Reporting group description
    Patient on the research (sequential) arm received intravenous nab-paclitaxel at 125mg/m2 on Day 1, 8 and 15, and intravenous gemcitabine at 1000mg/m2 on Day 2, 9 and 16 of a 4-weekly cycle for 6 cycles. Research bloods were taken from these patients on Cycle 1 Day 1, 2, 8, 9, 15 and 16 in the first instance, and then on Day 1 of each subsequent cycle.

    Reporting group values
    Concomitant Sequential Total
    Number of subjects
    75 71 146
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    0
        Children (2-11 years)
    0
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    all patients randomised
    Units: years
        median (full range (min-max))
    67.1 (48.0 to 82.3) 63.4 (44.8 to 76.8) -
    Gender categorical
    all patients randomised
    Units: Subjects
        Female
    35 28 63
        Male
    40 43 83
    Site of Primary Disease
    all patients randomised
    Units: Subjects
        Head
    35 34 69
        Body
    19 20 39
        Tail
    21 17 38
    Are Liver Metastases Present?
    all patients randomised
    Units: Subjects
        yes
    62 60 122
        no
    13 11 24
    Karnofsky Performance Status
    all patients randomised
    Units: Subjects
        70
    6 11 17
        80
    19 20 39
        90
    33 22 55
        100
    17 18 35

    End points

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    End points reporting groups
    Reporting group title
    Concomitant
    Reporting group description
    Patients on the control (concomitant) arm received intravenous nab-paclitaxel at 125mg/m2 immediately followed by intravenous gemcitabine at 1000mg/m2 on Days 1, 8 and 15 of a 4-weekly cycle for 6 cycles. Research bloods were taken from these patients on Cycle 1 Day 1, 8 and 15 in the first instance, and then on Day 1 of each subsequent cycle.

    Reporting group title
    Sequential
    Reporting group description
    Patient on the research (sequential) arm received intravenous nab-paclitaxel at 125mg/m2 on Day 1, 8 and 15, and intravenous gemcitabine at 1000mg/m2 on Day 2, 9 and 16 of a 4-weekly cycle for 6 cycles. Research bloods were taken from these patients on Cycle 1 Day 1, 2, 8, 9, 15 and 16 in the first instance, and then on Day 1 of each subsequent cycle.

    Primary: Progression Free Survival

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    End point title
    Progression Free Survival [1]
    End point description
    Progression free survival (PFS) was calculated from date of randomisation to the date of clinical/radiological progression or death from any cause, whichever occurs first. CT scans were performed on an 8-weekly basis.
    End point type
    Primary
    End point timeframe
    Patients were assessed every 4 weeks until disease progression. Patients were assessed 3-monthly after disease progression for a minimum of 1 year.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses to compare the two groups have been performed as the study is not powered to compare the arms.
    End point values
    Concomitant Sequential
    Number of subjects analysed
    75 [2]
    71 [3]
    Units: months
        median (confidence interval 95%)
    4.0 (3.0 to 5.4)
    5.6 (3.6 to 7.2)
    Notes
    [2] - The observed 6-month PFS and median PFS was 32% in the concomitant arm
    [3] - The observed 6-month PFS and median PFS was 46% in the sequential arm
    No statistical analyses for this end point

    Secondary: Objective Response

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    End point title
    Objective Response
    End point description
    measured according to RECIST V1.1
    End point type
    Secondary
    End point timeframe
    Assessed 8-weekly from randomisation to disease progression
    End point values
    Concomitant Sequential
    Number of subjects analysed
    61 [4]
    56 [5]
    Units: subjects
        Complete Response/Partial Response
    19
    29
        Stable Disease/Progressive Disease
    42
    27
    Notes
    [4] - 14 patients on the concomitant arm were not evaluable
    [5] - 15 patient in the sequential arm were not evaluable.
    No statistical analyses for this end point

    Secondary: Safety

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    End point title
    Safety
    End point description
    Any untoward medical occurrence in a patient or clinical trial subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment was reported. These events were reported as per the CTCAE v4.03 guidelines
    End point type
    Secondary
    End point timeframe
    from date of informed consent to 30-days post-treatment
    End point values
    Concomitant Sequential
    Number of subjects analysed
    74 [6]
    68 [7]
    Units: subjects
        Patients with Adverse Events Grade 3 and above
    61
    66
        Patients with Adverse Events Grade 1 -2
    13
    2
    Notes
    [6] - On the concomitant arm; 1 patient did not receive treatment; 193 G3+ AEs were reported.
    [7] - On the sequential arm: 3 patients did not receive treatment; 314 G3+ AEs were reported.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events (AE's) reported were from the starting protocol treatment regimen until 30 days after the last administration of study drugs.
    Adverse event reporting additional description
    Severity of all AE's has been reported as one of the secondary endpoints. Although a total of number of fatal AEs=15, the treatment related AE caused death = 7 (3 Concomitant, 4 Sequential).
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    CTCAE
    Dictionary version
    4.03
    Reporting groups
    Reporting group title
    Sequential
    Reporting group description
    -

    Reporting group title
    Concomitant
    Reporting group description
    -

    Serious adverse events
    Sequential Concomitant
    Total subjects affected by serious adverse events
         subjects affected / exposed
    59 / 68 (86.76%)
    48 / 74 (64.86%)
         number of deaths (all causes)
    59
    64
         number of deaths resulting from adverse events
    10
    5
    Vascular disorders
    Vascular disorders - Other, splenic artery pseudoaneurysm
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thromboembolic event
         subjects affected / exposed
    3 / 68 (4.41%)
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Surgical and medical procedures
    Surgical and medical procedures - Other, anorectal surgery
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    13 / 68 (19.12%)
    13 / 74 (17.57%)
         occurrences causally related to treatment / all
    1 / 16
    2 / 21
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusion
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    1 / 68 (1.47%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations - Other, hepatic enzyme increased
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    7 / 68 (10.29%)
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    5 / 9
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations - Other, deranged liver function tests
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Heart failure
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    10 / 68 (14.71%)
    9 / 74 (12.16%)
         occurrences causally related to treatment / all
    5 / 10
    4 / 10
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Anemia
         subjects affected / exposed
    2 / 68 (2.94%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Hypoxia
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dyspnea
         subjects affected / exposed
    3 / 68 (4.41%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    2 / 68 (2.94%)
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders - Other, lung abscess
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Stroke
         subjects affected / exposed
    2 / 68 (2.94%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 68 (1.47%)
    3 / 74 (4.05%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 68 (1.47%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhea
         subjects affected / exposed
    2 / 68 (2.94%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jejunal obstruction
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 68 (2.94%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstruction gastric
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal hemorrhage
         subjects affected / exposed
    2 / 68 (2.94%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Esophagitis
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 68 (2.94%)
    6 / 74 (8.11%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric hemorrhage
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileal obstruction
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal hemorrhage
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucositis oral
         subjects affected / exposed
    2 / 68 (2.94%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 68 (1.47%)
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Gallbladder obstruction
         subjects affected / exposed
    1 / 68 (1.47%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hepatobiliary disorders - Other, biliary obstruction
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders - Other, cholangitis
         subjects affected / exposed
    1 / 68 (1.47%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hepatobiliary disorders - Other, jaundice and hepatorenal syndrome
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders - Other, biliary sepsis
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    2 / 68 (2.94%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 68 (2.94%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatremia
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anorexia
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    4 / 68 (5.88%)
    3 / 74 (4.05%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Biliary tract infection
         subjects affected / exposed
    4 / 68 (5.88%)
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anorectal infection
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations - Other, pneumonia
         subjects affected / exposed
    1 / 68 (1.47%)
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    Bronchial infection
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter related infection
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations - Other, infection unknown
         subjects affected / exposed
    1 / 68 (1.47%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations - Other, viral illness
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 68 (1.47%)
    3 / 74 (4.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    4 / 68 (5.88%)
    4 / 74 (5.41%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Skin infection
         subjects affected / exposed
    1 / 68 (1.47%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory infection
         subjects affected / exposed
    0 / 68 (0.00%)
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed
    5 / 68 (7.35%)
    4 / 74 (5.41%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Sequential Concomitant
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    67 / 68 (98.53%)
    69 / 74 (93.24%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    7
    Hot flashes
         subjects affected / exposed
    2 / 68 (2.94%)
    2 / 74 (2.70%)
         occurrences all number
    2
    2
    Hypertension
         subjects affected / exposed
    4 / 68 (5.88%)
    4 / 74 (5.41%)
         occurrences all number
    5
    4
    Hypotension
         subjects affected / exposed
    6 / 68 (8.82%)
    4 / 74 (5.41%)
         occurrences all number
    10
    4
    Superficial thrombophlebitis
         subjects affected / exposed
    0 / 68 (0.00%)
    2 / 74 (2.70%)
         occurrences all number
    0
    2
    Phlebitis
         subjects affected / exposed
    0 / 68 (0.00%)
    4 / 74 (5.41%)
         occurrences all number
    0
    4
    Thromboembolic event
         subjects affected / exposed
    8 / 68 (11.76%)
    3 / 74 (4.05%)
         occurrences all number
    8
    3
    Vascular disorders - Other, varicose vein pain
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    Surgical and medical procedures
    Surgical and medical procedures - Other, elective stoma reversal
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    Surgical and medical procedures - Other, wart removal
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Immune system disorders
    Allergic reaction
         subjects affected / exposed
    1 / 68 (1.47%)
    1 / 74 (1.35%)
         occurrences all number
    1
    1
    Anaphylaxis
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    52 / 68 (76.47%)
    52 / 74 (70.27%)
         occurrences all number
    165
    126
    Chills
         subjects affected / exposed
    10 / 68 (14.71%)
    6 / 74 (8.11%)
         occurrences all number
    16
    7
    Flu like symptoms
         subjects affected / exposed
    9 / 68 (13.24%)
    10 / 74 (13.51%)
         occurrences all number
    21
    16
    General disorders and administration site conditions - Other, Fall in performance status
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions - Other, fall in performance score
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Fever
         subjects affected / exposed
    19 / 68 (27.94%)
    14 / 74 (18.92%)
         occurrences all number
    29
    19
    General disorders and administration site conditions - Other, common cold
         subjects affected / exposed
    1 / 68 (1.47%)
    1 / 74 (1.35%)
         occurrences all number
    2
    1
    General disorders and administration site conditions - Other, drop in performance score
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Edema face
         subjects affected / exposed
    1 / 68 (1.47%)
    2 / 74 (2.70%)
         occurrences all number
    1
    3
    Edema limbs
         subjects affected / exposed
    22 / 68 (32.35%)
    24 / 74 (32.43%)
         occurrences all number
    35
    31
    Localized edema
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    Infusion site extravasation
         subjects affected / exposed
    2 / 68 (2.94%)
    0 / 74 (0.00%)
         occurrences all number
    2
    0
    Malaise
         subjects affected / exposed
    2 / 68 (2.94%)
    1 / 74 (1.35%)
         occurrences all number
    2
    1
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 68 (0.00%)
    3 / 74 (4.05%)
         occurrences all number
    0
    4
    Pain
         subjects affected / exposed
    3 / 68 (4.41%)
    1 / 74 (1.35%)
         occurrences all number
    3
    1
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 68 (1.47%)
    2 / 74 (2.70%)
         occurrences all number
    1
    2
    Anxiety
         subjects affected / exposed
    3 / 68 (4.41%)
    2 / 74 (2.70%)
         occurrences all number
    3
    3
    Confusion
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    Depression
         subjects affected / exposed
    5 / 68 (7.35%)
    2 / 74 (2.70%)
         occurrences all number
    5
    3
    Restlessness
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders - Other, low mood
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Insomnia
         subjects affected / exposed
    9 / 68 (13.24%)
    7 / 74 (9.46%)
         occurrences all number
    9
    9
    Suicidal ideation
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Reproductive system and breast disorders - Other, lump
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    Vaginal hemorrhage
         subjects affected / exposed
    2 / 68 (2.94%)
    1 / 74 (1.35%)
         occurrences all number
    2
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 68 (1.47%)
    2 / 74 (2.70%)
         occurrences all number
    1
    2
    Bruising
         subjects affected / exposed
    0 / 68 (0.00%)
    2 / 74 (2.70%)
         occurrences all number
    0
    2
    Injury, poisoning and procedural complications - Other, wound
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications - small wounds on both arms
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    Spinal fracture
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    10 / 68 (14.71%)
    3 / 74 (4.05%)
         occurrences all number
    16
    3
    Alanine aminotransferase increased
         subjects affected / exposed
    10 / 68 (14.71%)
    7 / 74 (9.46%)
         occurrences all number
    18
    15
    Alkaline phosphatase increased
         subjects affected / exposed
    7 / 68 (10.29%)
    8 / 74 (10.81%)
         occurrences all number
    17
    14
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 68 (5.88%)
    0 / 74 (0.00%)
         occurrences all number
    4
    0
    GGT increased
         subjects affected / exposed
    4 / 68 (5.88%)
    14 / 74 (18.92%)
         occurrences all number
    10
    19
    Creatinine increased
         subjects affected / exposed
    2 / 68 (2.94%)
    2 / 74 (2.70%)
         occurrences all number
    3
    2
    Electrocardiogram QT corrected interval prolonged
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    INR increased
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    Investigations - Other, c-reactive protein increased
         subjects affected / exposed
    4 / 68 (5.88%)
    2 / 74 (2.70%)
         occurrences all number
    6
    2
    Investigations - Other, creatinine decreased
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    Investigations - Other, liver function test increased
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    Investigations - Other, neutrophil count increased
         subjects affected / exposed
    0 / 68 (0.00%)
    2 / 74 (2.70%)
         occurrences all number
    0
    2
    Investigations - Other, platelet count increased
         subjects affected / exposed
    1 / 68 (1.47%)
    1 / 74 (1.35%)
         occurrences all number
    4
    1
    Investigations - Other, transaminases increased
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    4
    0
    Investigations - Other, urea increased
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    Investigations - Other, white blood cell increased
         subjects affected / exposed
    1 / 68 (1.47%)
    2 / 74 (2.70%)
         occurrences all number
    1
    2
    Lymphocyte count decreased
         subjects affected / exposed
    1 / 68 (1.47%)
    3 / 74 (4.05%)
         occurrences all number
    1
    12
    Platelet count decreased
         subjects affected / exposed
    14 / 68 (20.59%)
    32 / 74 (43.24%)
         occurrences all number
    35
    67
    Neutrophil count decreased
         subjects affected / exposed
    45 / 68 (66.18%)
    30 / 74 (40.54%)
         occurrences all number
    136
    60
    Weight loss
         subjects affected / exposed
    5 / 68 (7.35%)
    5 / 74 (6.76%)
         occurrences all number
    5
    5
    Weight gain
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    White blood cell decreased
         subjects affected / exposed
    12 / 68 (17.65%)
    12 / 74 (16.22%)
         occurrences all number
    40
    25
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders - Other, tachycardia of unknown origin.
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Sinus tachycardia
         subjects affected / exposed
    3 / 68 (4.41%)
    2 / 74 (2.70%)
         occurrences all number
    3
    3
    Palpitations
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Sinus bradycardia
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    15 / 68 (22.06%)
    5 / 74 (6.76%)
         occurrences all number
    19
    6
    Hiccups
         subjects affected / exposed
    3 / 68 (4.41%)
    5 / 74 (6.76%)
         occurrences all number
    7
    9
    Epistaxis
         subjects affected / exposed
    3 / 68 (4.41%)
    9 / 74 (12.16%)
         occurrences all number
    3
    9
    Dyspnea
         subjects affected / exposed
    15 / 68 (22.06%)
    17 / 74 (22.97%)
         occurrences all number
    19
    24
    Hypoxia
         subjects affected / exposed
    2 / 68 (2.94%)
    0 / 74 (0.00%)
         occurrences all number
    2
    0
    Respiratory, thoracic and mediastinal disorders - Other, coryzal symptoms
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders - Other, haemoptysis
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders - Other, rhinorrhoea
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Hoarseness
         subjects affected / exposed
    1 / 68 (1.47%)
    1 / 74 (1.35%)
         occurrences all number
    1
    1
    Sinus disorder
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Nasal congestion
         subjects affected / exposed
    2 / 68 (2.94%)
    0 / 74 (0.00%)
         occurrences all number
    2
    0
    Sore throat
         subjects affected / exposed
    7 / 68 (10.29%)
    2 / 74 (2.70%)
         occurrences all number
    7
    2
    Pleural effusion
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Postnasal drip
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    Wheezing
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    Productive cough
         subjects affected / exposed
    6 / 68 (8.82%)
    3 / 74 (4.05%)
         occurrences all number
    7
    5
    Pneumonitis
         subjects affected / exposed
    1 / 68 (1.47%)
    1 / 74 (1.35%)
         occurrences all number
    1
    1
    Voice alteration
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders - Other, Blood tinged secretions
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Blood and lymphatic system disorders - Other, pancytopenia
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Febrile neutropenia
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Anemia
         subjects affected / exposed
    31 / 68 (45.59%)
    31 / 74 (41.89%)
         occurrences all number
    109
    65
    Nervous system disorders
    Aphonia
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Dizziness
         subjects affected / exposed
    7 / 68 (10.29%)
    5 / 74 (6.76%)
         occurrences all number
    10
    6
    Dysarthria
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    Dysesthesia
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    Dysgeusia
         subjects affected / exposed
    11 / 68 (16.18%)
    8 / 74 (10.81%)
         occurrences all number
    12
    9
    Headache
         subjects affected / exposed
    4 / 68 (5.88%)
    6 / 74 (8.11%)
         occurrences all number
    5
    8
    Lethargy
         subjects affected / exposed
    14 / 68 (20.59%)
    7 / 74 (9.46%)
         occurrences all number
    29
    10
    Nervous system disorders - Other, footdrop
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    Nervous system disorders - Other, posterior reversible encephalopathy syndrome
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    Syncope
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Paresthesia
         subjects affected / exposed
    4 / 68 (5.88%)
    4 / 74 (5.41%)
         occurrences all number
    5
    6
    Somnolence
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    Nervous system disorders - Other, reduced sensation
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Neuralgia
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    2
    0
    Tremor
         subjects affected / exposed
    1 / 68 (1.47%)
    1 / 74 (1.35%)
         occurrences all number
    1
    1
    Peripheral sensory neuropathy
         subjects affected / exposed
    20 / 68 (29.41%)
    20 / 74 (27.03%)
         occurrences all number
    32
    34
    Peripheral motor neuropathy
         subjects affected / exposed
    2 / 68 (2.94%)
    0 / 74 (0.00%)
         occurrences all number
    4
    0
    Vasovagal reaction
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Presyncope
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Eye pain
         subjects affected / exposed
    1 / 68 (1.47%)
    1 / 74 (1.35%)
         occurrences all number
    1
    1
    Flashing lights
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    Dry eye
         subjects affected / exposed
    2 / 68 (2.94%)
    0 / 74 (0.00%)
         occurrences all number
    3
    0
    Eye disorders - Other, sticky eye
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Eye disorders - Other, vision change
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Eye disorders - Other, conjunctival haemorrhage
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Eye disorders - Other, bloodshot eye
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Eye disorders - Other, conjuctival hemorrhage
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Ear and labyrinth disorders - Other, blocked ear
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    Ear pain
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    External ear inflammation
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Tinnitus
         subjects affected / exposed
    2 / 68 (2.94%)
    1 / 74 (1.35%)
         occurrences all number
    2
    1
    Gastrointestinal disorders
    Bloating
         subjects affected / exposed
    5 / 68 (7.35%)
    3 / 74 (4.05%)
         occurrences all number
    8
    4
    Abdominal distension
         subjects affected / exposed
    2 / 68 (2.94%)
    1 / 74 (1.35%)
         occurrences all number
    2
    1
    Abdominal pain
         subjects affected / exposed
    24 / 68 (35.29%)
    24 / 74 (32.43%)
         occurrences all number
    35
    34
    Anal pain
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    2
    Flatulence
         subjects affected / exposed
    3 / 68 (4.41%)
    1 / 74 (1.35%)
         occurrences all number
    3
    1
    Gastroesophageal reflux disease
         subjects affected / exposed
    5 / 68 (7.35%)
    1 / 74 (1.35%)
         occurrences all number
    5
    2
    Gastrointestinal disorders - Other, dry lips
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    Ascites
         subjects affected / exposed
    3 / 68 (4.41%)
    5 / 74 (6.76%)
         occurrences all number
    3
    6
    Gastrointestinal disorders - Other, oral thrush
         subjects affected / exposed
    7 / 68 (10.29%)
    1 / 74 (1.35%)
         occurrences all number
    8
    1
    Gastrointestinal disorders - Other, pneumatosis
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders - Other, right inguinal hernia
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders - Other, steatorrhea
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders - Other, tenesmus
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Dry mouth
         subjects affected / exposed
    6 / 68 (8.82%)
    3 / 74 (4.05%)
         occurrences all number
    6
    4
    Dysphagia
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Colitis
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Hemorrhoids
         subjects affected / exposed
    2 / 68 (2.94%)
    2 / 74 (2.70%)
         occurrences all number
    2
    2
    Hemorrhoidal hemorrhage
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Constipation
         subjects affected / exposed
    29 / 68 (42.65%)
    26 / 74 (35.14%)
         occurrences all number
    42
    36
    Gastrointestinal disorders - Other, oedematous bowel
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Diarrhea
         subjects affected / exposed
    34 / 68 (50.00%)
    34 / 74 (45.95%)
         occurrences all number
    83
    70
    Dyspepsia
         subjects affected / exposed
    5 / 68 (7.35%)
    1 / 74 (1.35%)
         occurrences all number
    5
    1
    Obstruction gastric
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    Rectal hemorrhage
         subjects affected / exposed
    2 / 68 (2.94%)
    1 / 74 (1.35%)
         occurrences all number
    3
    2
    Mucositis oral
         subjects affected / exposed
    31 / 68 (45.59%)
    22 / 74 (29.73%)
         occurrences all number
    55
    32
    Oral pain
         subjects affected / exposed
    2 / 68 (2.94%)
    3 / 74 (4.05%)
         occurrences all number
    2
    3
    Nausea
         subjects affected / exposed
    36 / 68 (52.94%)
    35 / 74 (47.30%)
         occurrences all number
    86
    58
    Toothache
         subjects affected / exposed
    1 / 68 (1.47%)
    1 / 74 (1.35%)
         occurrences all number
    1
    1
    Vomiting
         subjects affected / exposed
    34 / 68 (50.00%)
    23 / 74 (31.08%)
         occurrences all number
    51
    38
    Stomach pain
         subjects affected / exposed
    0 / 68 (0.00%)
    2 / 74 (2.70%)
         occurrences all number
    0
    2
    Hepatobiliary disorders
    Hepatobiliary disorders - Other, cholangitis
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Hepatobiliary disorders - Other, ductal obstruction
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 68 (2.94%)
    0 / 74 (0.00%)
         occurrences all number
    3
    0
    Cystitis noninfective
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Chronic kidney disease
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    Hematuria
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    Renal and urinary disorders - Other, dysuria
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Urinary frequency
         subjects affected / exposed
    3 / 68 (4.41%)
    0 / 74 (0.00%)
         occurrences all number
    3
    0
    Urinary tract pain
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Urinary urgency
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Urinary retention
         subjects affected / exposed
    1 / 68 (1.47%)
    1 / 74 (1.35%)
         occurrences all number
    1
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    33 / 68 (48.53%)
    26 / 74 (35.14%)
         occurrences all number
    51
    37
    Hyperhidrosis
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    2
    Dry skin
         subjects affected / exposed
    6 / 68 (8.82%)
    5 / 74 (6.76%)
         occurrences all number
    7
    5
    Erythema multiforme
         subjects affected / exposed
    2 / 68 (2.94%)
    4 / 74 (5.41%)
         occurrences all number
    4
    5
    Skin and subcutaneous tissue disorders - Other, changes to skin of eye
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    Rash acneiform
         subjects affected / exposed
    5 / 68 (7.35%)
    4 / 74 (5.41%)
         occurrences all number
    10
    7
    Rash maculo-papular
         subjects affected / exposed
    18 / 68 (26.47%)
    8 / 74 (10.81%)
         occurrences all number
    21
    13
    Scalp pain
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders - Other, bleeding of forehead cut
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders - Other, boil
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Pruritus
         subjects affected / exposed
    8 / 68 (11.76%)
    7 / 74 (9.46%)
         occurrences all number
    8
    11
    Skin and subcutaneous tissue disorders - Other, foot corn
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders - Other, nail pain
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders - Other, rash
         subjects affected / exposed
    1 / 68 (1.47%)
    2 / 74 (2.70%)
         occurrences all number
    1
    2
    Skin and subcutaneous tissue disorders - Other, red spots
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders - Other, wart
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Skin ulceration
         subjects affected / exposed
    2 / 68 (2.94%)
    2 / 74 (2.70%)
         occurrences all number
    2
    2
    Nail loss
         subjects affected / exposed
    1 / 68 (1.47%)
    1 / 74 (1.35%)
         occurrences all number
    1
    1
    Skin and subcutaneous tissue disorders - Other, cutaneous toxicity
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    3
    0
    Pain of skin
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Palmar-plantar erythrodysesthesia syndrome
         subjects affected / exposed
    5 / 68 (7.35%)
    0 / 74 (0.00%)
         occurrences all number
    7
    0
    Nail discoloration
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    Urticaria
         subjects affected / exposed
    3 / 68 (4.41%)
    0 / 74 (0.00%)
         occurrences all number
    4
    0
    Purpura
         subjects affected / exposed
    1 / 68 (1.47%)
    1 / 74 (1.35%)
         occurrences all number
    1
    1
    Skin and subcutaneous tissue disorders - Other, erythema
         subjects affected / exposed
    1 / 68 (1.47%)
    1 / 74 (1.35%)
         occurrences all number
    2
    1
    Skin hyperpigmentation
         subjects affected / exposed
    3 / 68 (4.41%)
    1 / 74 (1.35%)
         occurrences all number
    4
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 68 (5.88%)
    7 / 74 (9.46%)
         occurrences all number
    4
    9
    Arthritis
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Back pain
         subjects affected / exposed
    11 / 68 (16.18%)
    10 / 74 (13.51%)
         occurrences all number
    16
    12
    Bone pain
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Generalized muscle weakness
         subjects affected / exposed
    4 / 68 (5.88%)
    2 / 74 (2.70%)
         occurrences all number
    6
    2
    Myalgia
         subjects affected / exposed
    5 / 68 (7.35%)
    5 / 74 (6.76%)
         occurrences all number
    7
    8
    Muscle weakness lower limb
         subjects affected / exposed
    3 / 68 (4.41%)
    2 / 74 (2.70%)
         occurrences all number
    3
    2
    Musculoskeletal and connective tissue disorders - Other, cachexia
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders - Other, groin pain
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    Joint effusion
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders - Other, myoclonic Jerks
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders - Other, rib pain
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders - Other, shoulder pain
         subjects affected / exposed
    3 / 68 (4.41%)
    1 / 74 (1.35%)
         occurrences all number
    3
    1
    Musculoskeletal and connective tissue disorders - Other, stiffness in legs
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    4
    0
    Neck pain
         subjects affected / exposed
    1 / 68 (1.47%)
    1 / 74 (1.35%)
         occurrences all number
    1
    1
    Pain in extremity
         subjects affected / exposed
    7 / 68 (10.29%)
    7 / 74 (9.46%)
         occurrences all number
    9
    8
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    25 / 68 (36.76%)
    25 / 74 (33.78%)
         occurrences all number
    65
    36
    Hyperglycemia
         subjects affected / exposed
    2 / 68 (2.94%)
    1 / 74 (1.35%)
         occurrences all number
    3
    1
    Dehydration
         subjects affected / exposed
    5 / 68 (7.35%)
    0 / 74 (0.00%)
         occurrences all number
    5
    0
    Hyperkalemia
         subjects affected / exposed
    2 / 68 (2.94%)
    0 / 74 (0.00%)
         occurrences all number
    3
    0
    Hypoalbuminemia
         subjects affected / exposed
    12 / 68 (17.65%)
    3 / 74 (4.05%)
         occurrences all number
    19
    8
    Hypocalcemia
         subjects affected / exposed
    4 / 68 (5.88%)
    4 / 74 (5.41%)
         occurrences all number
    9
    5
    Hypokalemia
         subjects affected / exposed
    5 / 68 (7.35%)
    3 / 74 (4.05%)
         occurrences all number
    11
    4
    Hypomagnesemia
         subjects affected / exposed
    3 / 68 (4.41%)
    1 / 74 (1.35%)
         occurrences all number
    3
    1
    Hyponatremia
         subjects affected / exposed
    3 / 68 (4.41%)
    5 / 74 (6.76%)
         occurrences all number
    3
    6
    Hypophosphatemia
         subjects affected / exposed
    1 / 68 (1.47%)
    1 / 74 (1.35%)
         occurrences all number
    1
    2
    Infections and infestations
    Eye infection
         subjects affected / exposed
    2 / 68 (2.94%)
    0 / 74 (0.00%)
         occurrences all number
    2
    0
    Gum infection
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Catheter related infection
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    2
    0
    Device related infection
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    Infections and infestations - Other, finger infection
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    Infections and infestations - Other, infected toe
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    2
    0
    Infections and infestations - Other, infection unknown
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    Infections and infestations - Other, Insect bite to right forearm
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations - Other, line infection
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations - Other, oral infection
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations - Other, oral thrush
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations - Other, pneumonia
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations - Other, pseudomonas aeruginosa infection
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations - Other, shingles
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    Lip infection
         subjects affected / exposed
    3 / 68 (4.41%)
    2 / 74 (2.70%)
         occurrences all number
    3
    2
    Sepsis
         subjects affected / exposed
    1 / 68 (1.47%)
    2 / 74 (2.70%)
         occurrences all number
    1
    2
    Mucosal infection
         subjects affected / exposed
    1 / 68 (1.47%)
    4 / 74 (5.41%)
         occurrences all number
    1
    4
    Papulopustular rash
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    Skin infection
         subjects affected / exposed
    6 / 68 (8.82%)
    2 / 74 (2.70%)
         occurrences all number
    9
    2
    Nail infection
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Small intestine infection
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    2
    0
    Lung infection
         subjects affected / exposed
    11 / 68 (16.18%)
    3 / 74 (4.05%)
         occurrences all number
    13
    3
    Vaginal infection
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    Tooth infection
         subjects affected / exposed
    2 / 68 (2.94%)
    2 / 74 (2.70%)
         occurrences all number
    2
    2
    Penile infection
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory infection
         subjects affected / exposed
    7 / 68 (10.29%)
    2 / 74 (2.70%)
         occurrences all number
    9
    2
    Urinary tract infection
         subjects affected / exposed
    6 / 68 (8.82%)
    4 / 74 (5.41%)
         occurrences all number
    6
    4
    Pharyngitis
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    1
    Wound infection
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 May 2014
    Addition of new dose modifications, safety information for Abraxane and Gemcitabine combination therapy, new sites and changes to PI
    27 Jan 2015
    Clarification of dose delay timelines, clarification of eligibility criteria, addition of instructions for treating patients with hepatic impairment and change to team contact details
    14 Oct 2015
    Increase of recruitment total from 120 patients to 146 patients, clarification of statistical analysis plan and calculation of sample size in accordance with the evaluable patient criteria.
    04 Jan 2016
    Changes to the patient information sheet and protocol - including change to number of participating sites, number of patients on each arm required to assess end points, clarification of the inclusion criterion addressing the provision of tumour samples, clarification of IMP SmPC-particulate matter, clarification of the rules regarding dose escalation, change to the requirements for the follow-up assessments

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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